title: Inhibition of myosin light chain kinase can be targeted for the development of new therapies against herpes simplex virus type-1 infection.
abstract: BACKGROUND
  Herpes simplex virus type-1 (HSV-1) is the leading cause of infectious blindness worldwide. Through a multistep process, HSV-1 enters into naturally susceptible human corneal epithelial (HCE) cells where it establishes an optimal environment for viral replication and spread. HSV-1 employment of cytoskeletal proteins, kinases, and cell signalling pathways is crucial for the entry process.
  
  
  METHODS
  Here we demonstrate that non-muscle myosin IIA (NM-IIA) and/or a myosin activating kinase, myosin light chain kinase (MLCK), can be targeted for the development of new and effective therapies against HSV-1. HCE cells were incubated with MLCK inhibitors ML-7 and ML-9 and NM-IIA inhibitor blebbistatin. Following the application of inhibitors, HSV-1 entry and spread to neighbouring HCE cells was evaluated.
  
  
  RESULTS
  Upon application of MLCK inhibitors ML-7 and ML-9 and NM-IIA inhibitor blebbistatin, HSV-1 entry into HCE cells was significantly decreased. Furthermore, dramatic impairment of glycoprotein-mediated membrane fusion was seen in cells treated with MLCK inhibitors, thus establishing a role for MLCK activation in cell-to-cell fusion and multinucleated syncytial cell formation. These results also indicate that the activation of motor protein NM-IIA by MLCK is crucial for cytoskeletal changes required for HSV-1 infection of corneal cells.
  
  
  CONCLUSIONS
  We provide new evidence that NM-IIA and MLCK can be used as effective antiviral targets against ocular herpes.
authors.affiliation: Department of Ophthalmology & Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Thessicar E
authors.initials: TE
authors.lastname: Antoine
authors.forename: Deepak
authors.initials: D
authors.lastname: Shukla
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D004847:Epithelial Cells / Q000378:metabolism / Q000821:virology; D005110:Extracellular Space / Q000378:metabolism; D015726:Giant Cells / Q000187:drug effects; D006561:Herpes Simplex / Q000188:drug therapy / Q000201:enzymology*; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D020409:Molecular Motor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000037:antagonists & inhibitors / Q000378:metabolism; D009219:Myosin-Light-Chain Kinase / Q000037:antagonists & inhibitors*; D011485:Protein Binding; D010948:Viral Plaque Assay; D053586:Virus Internalization / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; C103814:MYH9 protein, human; D020409:Molecular Motor Proteins; D009219:Myosin-Light-Chain Kinase; D018995:Myosin Heavy Chains